Patients with acute hypoxemic respiratory failure associated with severe non-cardiogenic pulmonary edema exhibit a depressed ability to extract oxygen from the periphery. In these patients, a change in oxygen delivery (QO2 = cardiac output x arterial O2 content) caused by a change in cardiac output (Qt) is associated with a corresponding change in O2 uptake (VO2). With these changes in QO2 and VO2, mixed venous PO2 remains relatively constant at normal or high levels. By contrast, critically ill patients without respiratory failure show no dependence of VO2 on QO2 unless delivery falls below 330 ml/min/m2. An inability of peripheral tissues to extract sufficient oxygen to maintain aerobic metabolism may be caused by molecular diffusion limitation at the capillary level, due to an enhanced diffusion distance. Additionally, inefficient distribution of peripheral blood flow with overperfusion of low O2 extracting vessels and underperfusion of capillaries with high O2 uptake might explain an abnormal dependence of VO2 on QO2. Experimental studies are proposed to test the effects of increased or decreased hemoglobin P50 on the critical QO2 required for aerobic metabolism. Another group will clarify the relative contributions of altered P50 (Bohr effect) versus low pH in the enhanced peripheral O2 extraction efficiency reported during metabolic acidosis. Additional studies will test the influence of arteriolar tone on maintenance of VO2 by measuring critical QO2 and extraction during phenoxybenzamine blockade, hydralazine or low dose norepinephrine infusion. Other studies will examine the effects of intravascular coagulation or sepsis on the critical QO2 and extraction. A separate group will test the possibility that mild hypothermia may reduce VO2 to a greater extent than it lowers QO2, thereby providing a clinical tool for management of patients with increased critical QO2 and severe hypoxemia. Critical QO2 will be determined in each of these groups by measuring VO2 and lactic acid as QO2 is gradually reduced by plasmapheresis. Critical QO2 is determined in each animal from the QO2 below which VO2 is reduced. These studies will help to clarify the pathophysiological mechanisms responsible for a dependence of VO2 on QO2, and will help to uncover potentially therapeutic interventions for the maintenance of peripheral O2 extraction.